Download Immune Mechanisms Are Major Players in Cancer Karl Erik

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Immune Mechanisms Are Major Players in Cancer
Karl Erik Hellstrom and Ingegerd Hellstrom
Department of Pathology, Harborview Medical Center, University of Washington,
Seattle, Washington.
Corresponding Author: Karl Erik Hellstrom, Department of Pathology, University of
Washington, Harborview Medical Center, 325 9th Avenue, Seattle WA 09104. Phone:
206-897-5907; E-mail: [email protected]
Running Title: Sipuleucel-T Vaccination
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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Summary
Vaccination with sipuleucel-T produced IgG antibodies to secondary prostatic
carcinoma antigens and prolonged survival in some patients, and assaying for
antibodies may provide prognostic information and identify new vaccine targets.
Additional approaches to improve T-cell responses are needed to improve the clinical
efficacy.
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In this issue of Clinical Cancer Research, GuaThakurta and colleagues (1) demonstrate
IgG antibodies to non-targeted tumor antigens in some prostatic carcinoma patients
who were vaccinated with sipuleucel-T and showed that the antibodies were associated
with improved clinical outcome. Although the clinical efficacy of this treatment was
modest, much is being learned from the first human therapeutic cancer vaccine that will
lead to more efficacious such vaccines.
After many years of controversy, oncoimmunology is approaching the front-line
for cancer therapy. Coley reported over 100 years ago that injection of bacterial toxins
into advanced cancers induced a therapeutic response in 40 % of cases including the
rejection of tumors that were not injected, and Paul Ehrlich speculated over
immunological bullets for tumor destruction. Some 50 years later Prehn and others
demonstrated that mice immunized against a chemically induced syngeneic tumor
rejected transplanted cells from the same tumor, and that the rejection response was
primarily mediated by immune lymphocytes. Other studies showed that lymphoid cells in
peripheral blood from human cancer patients could recognize and kill the patients’
cultured tumor cells also when the patients had advanced disease, and mechanisms
which could inhibit this response began to be identified (2). However, controversy
prevailed for many years and many argued that spontaneous tumors, including those in
humans, cannot be recognized as foreign by the host’s immune system and gave
“reasons” why therapeutic vaccines cannot work.
The controversies subsided as more refined techniques were developed. Targets
of tumor-directed immune responses were identified at the molecular level (3), and
insight was gained about immune regulation including the role of costimulation via B7
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(CD80; CD86) and CD28 (4). For example, most tumors were found to not express B7
and transfecting them to express B7 dramatically increased their immunogenicity (5).
Additional costimulatory receptors (e.g., CD137, OX40) and ligands (e.g., CD137L)
were soon identified as were receptors (e.g., CTLA4, PD-1) and ligands (PDL-1, PDL-2)
which could inhibit the generation of an immune response. Importantly, manipulation of
the immune response by administering monoclonal antibodies (mAbs) to some of these
molecules was found to have strong anti-tumor activity in several preclinical models (68) including the complete regression and cure of large mouse tumors (9). The discovery
of toll-like receptors and their ligands as regulators of innate immune responses
provided other approaches to induce a strong anti-tumor response (10). Another
important contribution was the demonstration that the tumor microenvironment is highly
immunosuppressive and provides an obstacle to therapeutic tumor vaccination.
Cancer cells have a high mutation rate, variants which lack a particular target are
common, and selection for therapy resistance is a major concern for the use of anticancer drugs. Immune mechanisms have the potential to handle this problem and may
even benefit from it, since some mutations encode epitopes that are selective for the
individual tumor. A properly engaged anti-tumor immunity can target many different
epitopes which decreases the selection of immunoresistant variants. This can be
achieved either by using vaccines that comprise many tumor antigens or by inducing an
immune response to a primary tumor antigen with strong antigen (epitope) spreading. In
the latter case, targeting of the primary antigen induces an immune response including
destruction of some tumor cells and the production of immunostimulatory
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cytokines/lymphokines which facilitate the maturation of antigen-presenting dendritic
cells and the induction of a response also against non-targeted, secondary antigens.
A major event in cancer immunology was the approval by the FDA of sipuleucelT in 2010 to treat symptom-free patients with metastatic castration resistant prostatic
carcinoma. The patients are injected 3 times with their autologous blood lymphoid cells
that have been cultured with a fusion protein between prostatic acidic phosphatase (the
primary antigen) and GMCSF.
Unfortunately the clinical efficacy of Sipuleucel-T, while statistically significant, is
observed in just about 30% of patients and only as a few months prolonged survival
without detectable tumor shrinkage. This limited efficacy is in contrast to the therapeutic
responses that are seen in some cancer patients (melanoma in particular) after
treatment with immunomodulatory monoclonal antibodies (mAbs) such as a
combination of anti-CTLA4 plus anti-PD-1 (11). Impressive therapeutic efficacy has also
been demonstrated in patients with B cell lymphomas after adoptive transfer of
autologous T lymphocytes which have been engineered in vitro to target the tumor and
undergo many divisions in vivo (12).
Based on the encouraging findings with immunomodulatory mAbs and
engineered T cells we believe that efficacious immunotherapy will be developed also for
carcinomas of the prostate. For example, therapeutic vaccination might be combined
with immunomodulatory mAbs to decrease the impact of the immunosuppressive tumor
microenvironment and the mAbs may perhaps be delivered locally (9).
The report by GuhaThakurta and colleagues (1) is encouraging. It describes
‘blinded’ and Placebo-controlled studies on a large number of randomized patients and
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provides stronger evidence than any previous study that antigen spreading, detected as
IgG antibodies to secondary tumor antigens, can be induced in some of the patients
vaccinated against sipuleucel-T (Fig. 1). Antigen spreading is important since it can
dramatically increase the population of lymphoid cells that are engaged in the anti-tumor
response. It is noteworthy that those patients where antigen spreading was most
pronounced also had the best overall survival. Methods to effectively increase antigen
spreading may improve the efficacy of tumor vaccination.
The demonstration of IgG antibodies to secondary antigens that are
overexpressed in carcinoma of the prostate is important also by indicating that
antibodies to such antigens may serve as prognostic markers. This may be true also for
patients undergoing immunotherapy for other tumors, and one should try to find out
whether tumor destruction by chemotherapy also can induce antigen spreading. As
emphasized by GuhaThakurta and colleagues, an anti-tumor efficacy of the antibodies
shall not be dismissed, since antibodies can contribute to tumor destruction, e.g., by
mediating ADCC and CDC and/or by interfering with tumor promoting signaling (1). The
function of the antibodies needs, indeed, to be investigated.
Since the antibodies were of the IgG isotype, helper T cells were engaged by the
vaccination, and published studies, which are discussed by GuhaThakurta and
colleagues (1), have demonstrated both CD4 and CD8 cells in patients vaccinated with
Sipuleucel-T. However, much more needs to be learned about the cell-mediated
responses in the vaccinated patients, since high numbers of tumor-reactive T cells are
likely to be needed for immunological destruction of a tumor mass. Has antigen
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spreading expanded the number of tumor-reactive Th1 cells to the patients’ prostatic
carcinomas and are there are clinically feasible ways to further increase this number?
As pointed out by GuhaThakurta and colleagues (1), it may also be rewarding to
identify those antigens that most effectively induce an antibody response since they
may be good for use as primary target antigens to vaccinate against.
Acknowledgments
The authors thank Dr. Paul Abrams and Hans Olov Sjogren for many valuable
discussions.
Grant Support
K.E. Hellstrom and I. Hellstrom were supported by the NIH under award number
RO1CA134487.
References
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Humoral immune response against non-targeted tumor antigens after treatment with
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Feb 3. [Epub ahead of print].
2.
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Figure 1. Vaccination with PAP in the presence of GMCSF maturates APS and induces
an immune response to PAP. Cytokines induced by the response to the primary antigen
matures additional APC which take up and present secondary antigens released from
killed tumor cells. The tumor microenvironment remains immunosuppressive.
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Figure 1:
Vaccinated
PAP (s)+ GMCSF
Placebo
MHC II
TCR
MHC II
TH
APC
TH
APC
CD80/86 CD28
Tumor
cell
TCR
CD80/86 CD28
Tumor
cell
T reg
Tumor
cell
T reg
MDSC
Tumor
cell
MDSC
Tumor
cell
Tumor
cell
MDSC
T reg
Acid phosphatase
Cytokines
Various other epitopes
APC
TH
T reg
Anti- , anti- , anti- IgG
Cell-mediated immunity
not studied
MDSC
APC
TH
© 2015 American Association for Cancer Research
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Immune Mechanisms Are Major Players in Cancer
Karl Erik Hellstrom and Ingegerd Hellstrom
Clin Cancer Res Published OnlineFirst April 22, 2015.
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